Blood coagulation is a reaction in which serine protease precursors are successively activated by activated-form proteases, which finally generate thrombin thereby leading to fibrin formation. Thrombosis arises as a consequence of an excessively enhanced blood coagulation reaction that was caused by changes in the plasma coagulation and fibrinolytic system, and in the functions of platelets, leucocytes and vascular endothelial cells associated with the progression of various disease states. The initiating factor of the blood coagulation reaction is tissue factor. In acute coronary syndromes such as acute myocardial infarction and unstable angina, the blood coagulation reaction is triggered when tissue factor occurring in abundance in the plaques formed after the progression of arterial sclerosis is exposed to the blood due to the rhexis of plaques.
In the disseminated intravascular coagulation syndrome associated with sepsis and malignant tumors, activated monocytes and macrophages express tissue factor or tumor cells express tissue factor thereby causing enhanced blood coagulation. Once tissue factor comes into contact with the blood, the blood coagulation reaction proceeds in a very short period of time and leads to the formation of blood clots. Thus, in order to prevent thrombus formation, it is necessary to block blood coagulation reactions that may be triggered at any time or that may be constantly occurring. Therefore, an experimental model that exhibits a hypercoagulable state on a persistent basis is essential for the development of effective anti-thrombotic agents. In any of the conventionally known thrombotic models, thrombus formation is induced in a short period of time.
Thus, according to one aspect of the present invention, there is provided an experimental model in which a hypercoagulable state persists by bringing human tissue factor into contact with the blood on a persistent basis.
Blood coagulation is a reaction in which serine protease precursors are successively activated by activated-form proteases, which finally generate thrombin thereby leading to fibrin formation. Thrombosis arises as a consequence of an excessively enhanced blood coagulation reaction that was caused by changes in the plasma coagulation and fibrinolytic system, and in the functions of platelets, leucocytes and vascular endothelial cells associated with the progression of various disease states. The initiating factor of the blood coagulation reaction is tissue factor (TF).
In acute coronary syndromes such as acute myocardial infarction and unstable angina, the blood coagulation reaction is triggered when tissue factor occurring in abundance in the plaques formed after the progression of arterial sclerosis is exposed to the blood due to the rupture of plaques. In disseminated intravascular coagulation syndrome associated with sepsis and malignant tumors, activated monocytes and macrophages express TF or tumor cells express TF thereby leading to enhanced blood coagulation and this state persists. Once TF comes into contact with the blood, the blood coagulation reaction proceeds in a very short period of time leading to the formation of blood clots. Thus, in order to prevent thrombus formation, it is necessary to block blood coagulation reactions that may be triggered at any time or that may be constantly occurring. Therefore, as an effective anti-thrombotic agent, a drug is required that can block the persistence of the hypercoagulable state that is occurring on a constant basis.
Thus, according to the second aspect of the present invention, there is provided a novel preventive or therapeutic agent for diseases having a persistent hypercoagulable state.
Severe infections are often associated with abnormal coagulation, which induces disease states such as multiple organ failure and the disseminated intravascular coagulation syndrome, and represents a factor that aggravates the prognosis of the patient. The measures employed are thus considered to be important. In severe infections, systemic infections such as sepsis and, among them, lesions in the vascular endothelial cells have been implicated as the onset mechanism of organ disorders. In sepsis, and particular in sepsis caused by gram negative bacteria, a cellular component, lipopolysaccharide (LPS), plays an important role.
LPS liberated into the blood not only activates monocytes and thereby produces tissue factor (TF) leading to a hypercoagulable state, but produces and liberates cytokines such as TNF, IL-β and IL-8 and thereby activates neutrophils and vascular endothelial cells. The activated neutrophils adhere to the vascular endothelial cells to liberate cytotoxic substances such as active enzymes and elastases, which injure the vascular endothelial cells. In the vascular endothelial cells activated by cytokines or injured by neutrophils, the production of TF is enhanced which further progresses the hypercoagulable state. As a result, microthrombi occur systemically, which elicits circulatory failures in the organs leading to multiple organ failure.
Thus, there is a great need for the development of preventive or therapeutic agents for blood coagulable states caused by infections.
Thus, according to the third aspect of the present invention, there is provided a novel preventive or therapeutic agent for blood coagulable states caused by infections.
As a mechanism leading to the onset of venous thrombosis, venous stasis, damages to the venous wall, and hypercoagulabilyty are thought to play an important role. In particular, invasive events such as surgery, childbirth and trauma induce physical injuries to the vascular wall and abnormalities in the coagulation and fibrinolysis system, and decubitus after surgery induces a renous stasis. Not only the resulting blood clots in the vein induce circulatory failure in the limbs but the clots themselves enter into the blood circulation and flows into the pulmonary artery leading to fatal pulmonary embolism. Hence, the prevention of venous thrombosis itself is considered to be important. Thus, there is a need for the development of agents that can effectively prevent or treat venous thrombosis.
Thus, according to the fourth aspect of the present invention, there is provided a novel preventive or therapeutic agent for the treatment of venous thrombosis.
In arterial thrombosis, blood clots occur in the blood vessel having an advanced sclerosis, and the onset of the disease in the important organs such as the brain and the heart would be fatal in most cases. In particular, acute coronary syndromes such as unstable angina and acute myocardial infarction are believed to be dangerous disease states that could easily cause sudden death. Recently it was demonstrated that the rhexis of the arteriosclerotic plaques and the ensuing thrombus formation is an important factor in the onset mechanism of the disease.
It has also been demonstrated that tissue factor (TF), an initiating factor for thrombus formation, is being excessively expressed on the cell surface and the extracellular interstitium in the plaque, and thus it is believed that the exposure of tissue factor (TF) to the blood resulting from the rupture of plaques is a major factor for thrombus formation.
Thus, there is a great need for the development of a novel drug for preventing or treating arterial thrombosis.
Thus, according to the fifth aspect of the present invention, there is provided a novel preventive or therapeutic agent for arterial thrombosis.
Percutaneous transluminal coronary angioplasty (PTCA) occupies an important position in the treatment of coronary heart diseases. But restenosis that occurs several months after the operation hinders the effectiveness of the treating method and thus is posing a problem. As a cause of restenosis, it is becoming increasingly clear, thrombus formation during the acute phase and the subacute phase resulting from the injuries to endothelial cells is important. The contact with the blood of tissue factor (TF) expressed by the injured endothelial cells and the smooth muscles and fibroblasts in the subendothelial tissue is important for thrombus formation. The cells in the blood vessel wall grow so as to cover the resulting thrombi and thereby narrow the area of the lumen in the blood vessel. The growth of the blood vessel tissue per se and the constriction of the blood vessel diameter also contribute to the narrowing of the area of the lumen in the blood vessel, and they provide a direct factor for restenosis. Thus, there is a great need for a novel drug that can prevent or treat restenosis.
Thus, according to the sixth aspect of the present invention, there is provided a novel preventive or therapeutic agent for diseases caused by the hypertrophy of vascular media.